Degenerative diseases that result in the loss of photoreceptors, including Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP), are common causes of blindness in the developed world. These diseases largely spare the connections and functions of the retinal ganglion cells that link the retina to central targets in the brain. Therefore, the strategy of rendering retinal ganglion cells directly responsive to light holds a great deal of promise for developing therapies for these diseases. Light-sensitive ganglion cells would bypass the damaged photoreceptors, but take advantage of the normal visual pathways beyond the retina. Other laboratories have previously demonstrated that it is possible to express the light-activated cation channel, channelrhodopsin-2 (ChR2), in retinal cells. Studies have shown that in a rodent model of photoreceptor degeneration, expression of ChR2 can render retinal cells photosensitive. Light responses due to the expression of ChR2 in the retina are transmitted to the visual cortex, and can underlie rudimentary visual behaviors. A great deal of work remains to be done, however, before the use of ChR2 or similar light- activated molecules to treat retinal degenerative diseases could be contemplated in a clinical setting. This R21 proposal addresses two important issues that need to be tackled. Specific aim 1 will determine how best to obtain widespread, stable expression of ChR2 in retinal ganglion cells in a non- rodent model system, and whether such expression leads to visual responses in retinal ganglion cells that are transmitted to lateral geniculate nucleus and primary visual cortex cells. Specific aim 2 will determine whether the vision caused by the expression of ChR2 in retinal ganglion cells can either enhance or interfere with the development and adult function of normal visual pathways. Successful completion of these two aims will bring the field significantly closer to the goal of being able to translate light-activated channel technology into the clinic, and will provide preliminary data needed to apply for funding to determine whether this approach can be used to produce behaviorally useful vision in a retinal detachment model of blindness. PUBLIC HEALTH RELEVANCE: The long-term goal of this research is to develop methods to cure forms of blindness caused by the loss of photoreceptor function including Age-related Macular Degeneration and Retinitis Pigmentosa. Experiments will test whether artificially making retinal cells photosensitive through expression of light- activated ion channels is a promising approach to curing these diseases.